Lipophilic Carrier Research Articles

Ruthenium(II) complexes containing PEGylated N-heterocyclic carbene ligands for tunning biocompatibility in the fight against cancer

A synthetic procedure was designed for the preparation and characterization of Ag and Ru complexes containing NHC ligands functionalized with PEG fragments. Stability studies were conducted to gain insight of the species in water and other solvents like DMSO, or with reagents like imidazole as representative group for histidine amino acid. The presence of Cl atoms instead of H in the 4,5 positions of the N-heterocyclic carbene afforded higher water stability. The complexes containing PEG units must be considered inactive as anticancer agents. To enhance the anticancer activity of PEG-containing complexes, the balance between hydrophilicity and hydrophobicity was adjusted using a silane moiety, and an anionic carbosilane dendrimer as a lipophilic carrier.

Liposomes against Alzheimer's Disease: Current Research and Future Prospects.

Alzheimer's disease, the most common neurodegenerative disease, affects more than 60 million people worldwide, a number that is estimated to double by 2050. Alzheimer's disease is characterized by progressive memory loss, the impairment of behavior, and mood changes, as well as the disturbed daily routine of the patient. Although there are some active molecules that can be beneficial by halting the progression of the disease, the blood-brain barrier and other physiological barriers hinder their delivery and, consequently, the appropriate management of the disease. Therefore, drug delivery systems that effectively target and overcome the blood-brain barrier to reach the targeted brain area would improve treatment effectiveness. Liposomes are lipophilic carriers that consist of a phospholipid bilayer structure, simulating the physiological lipidic layer of the blood-brain barrier and enabling better delivery of the drug to the brain. Given that pure liposomes may have less targeting affinity than functionalized liposomes, modification with groups such as lactoferrin, poly(ethylene glycol), and transferrin may improve specificity. In this mini-review, we summarize the literature on the use of liposomes for the treatment of Alzheimer's disease, focusing on the functionalization moieties of liposomes. In addition, challenges in brain delivery are also discussed.

Evaluation of diclofenac emulgel prepared with sesame oil as a lipophilic carrier

Purpose: To investigate the suitability of sesame oil as an oily phase for diclofenac emulgel formulation.
 Methods: Different batches of emulgel comprising different proportions of oils (sesame oil and/or Labrafac CC), surfactants (Tween-80 and/or cremophor EL-30), and gelling agents (xanthan gum or gelatin) were prepared. The formulations were evaluated for rheology, syneresis, Fourier transform infrared (FTIR) spectroscopy, spreadability, extrudability, and anti-inflammatory activity.
 Results: Product characteristics of batches A2, A4, and A6 were not consistent with those of emulgels. Because Batch A1 showed characteristics that were the most stable, such as no pH changes, nonstatistically significant changes (p = 1.000) in the viscosity results, and least spectrum changes following FTIR investigation, it was selected as the best batch. It showed similar anti-inflammatory activity when compared with commercially available diclofenac emulgel, giving a 50 % higher anti-inflammatory effect than aqueous diclofenac dispersion. 
 Conclusion: Sesame oil is a potential lipophilic component in emulgel formulations for topical delivery of hydrophobic drugs.

Comparative study of the specific activity of soft application drugs with vinpocetine

In modern neurology, the main component of successful treatment of cerebrovascular pathology is pharmacotherapy. At the same time, the arsenal of effective medicines of evidence-based medicine in this area is quite limited. Vinpocetine (Cavinton) is one of the drugs that effectively selectively corrects cerebral perfusion. The use of alternative ways of absorption of vinpocetine (rectal and nasal) in certain soft application dosage forms will allow to significantly increase the bioavailability of the medicinal substance, reduce the level of adverse reactions from its use and expand the pharmacotherapeutic arsenal of domestic effective neuroprotective drugs. Taking into account the above, the employees of the Department of Medicines Technology of Zaporizhzhia State Medical University, on the basis of complex physical-chemical, pharmacotechnological, rheological and biopharmaceutical research, proposed rational formulations and technologies of two new soft application dosage forms of vinpocetine – rectal suppositories on a lipophilic basis and nasal cream on an emulsion basis for the therapy of arterial hypertension of II–III stages with cerebrovascular complications, reduction of the manifestation of neurological and/or mental symptoms in various forms of cerebral blood circulation insufficiency, consequences of a stroke, transient ischemic attack, etc. The aim of the work is to study the specific activity of the proposed innovative application dosage forms of vinpocetine. Materials and methods. Nasal ointment containing 0.5 % vinpocetine on an emulsion basis and rectal suppositories with vinpocetine 0.01 g on a lipophilic carrier were used as the object of preclinical studies, which ensure optimal release of the active pharmaceutical ingredient. The study of the specific activity of the developed medicinal forms of vinpocetine was carried out on a model of acute cerebrovascular accident of the type of ischemic stroke. Vinpocetin tablets (Astrapharm, Ukraine), which are used in neurological practice quite effectively and over a long period of time, were used as a comparison drug. Results. The comparative results showed that the appointment of all studied drugs led to an increase in motor activity. In addition, the administration of medicinal forms of vinpocetine reduced the development of cognitive and cognitive disorders after acute disorders of cerebral blood circulation. It was found that the highest result was shown by the group of animals that received a course of vinpocetine intranasally. In the groups of animals that received vinpocetine for 4 days, markers of oxidative stress – aldehyde phenylhydrazones and ketone phenylhydrazones – were significantly reduced. The highest activity was demonstrated by the pharmaceutical form of vinpocetin, which was used intranasally for 4 days. The introduction of dosage forms of vinpocetine exerted an energizing effect, which was expressed in an increase in the level of macroergic phosphates. Evidently, vinpocetine has a direct positive effect on the three-carbon sections of the Krebs cycle and increases the production of adenosine triphosphate (ATP). At the same time, the vinpocetine nasal cream applied intranasally for 4 days demonstrated the greatest energizing activity. Conclusions. Preclinical studies of the developed application soft medicines with vinpocetine on the model of acute cerebrovascular accident type ischemic stroke experimentally confirmed the expressed neuroprotective activity of rectal suppositories and nasal cream with vinpocetine and it was found that the effectiveness of therapy with these application medicinal forms is demonstrably higher than that in comparison with oral tablet means.

Can membrane composition traffic toxins? Mycolactone and preferential membrane interactions

Mycolactone is a cytotoxic and immunosuppressive macrolide produced by Mycobacterium ulcerans and the sole causative agent of the neglected tropical skin disease Buruli ulcer. The toxin acts by invading host cells and interacting with intracellular targets to disrupt multiple fundamental cellular processes. Mycolactone’s amphiphilic nature enables strong interactions with lipophilic environments, including cellular membranes; however, the specificity of these interactions and the role of membranes in the toxin’s pathogenicity remain unknown. It is likely that preferential interactions with lipophilic carriers play a key role in the toxin’s distribution in the host, which, if understood, could provide insights to aid in the development of needed diagnostics for Buruli ulcer disease. In this work, molecular dynamics simulations were combined with enhanced free-energy sampling to characterize mycolactone’s association with and permeation through models of the mammalian endoplasmic reticulum (ER) and plasma membranes (PMs). We find that increased order in the PMs not only leads to a different permeation mechanism compared with that in the ER membrane but also an energetic driving force for ER localization. Increased hydration, membrane deformation, and preferential interactions with unsaturated lipid tails stabilize the toxin in the ER membrane, while disruption of lipid packing is a destabilizing force in the PMs.

OVERVIEW OF MITOXANTRONE-A POTENTIAL CANDIDATE FOR TREATMENT OF BREAST CANCER

Anthraquinones are one of the popular classes of aromatic compounds which possess potential anticancer properties by suppressing the nucleic acid formation and proteins essential to the survival of cancerous cells. Mitoxantrone (MT) is an antibiotic and antineoplastic agent belonging to the anthracycline class of compounds which exhibit minimal incident of drug resistance. It is a synthetic anticancer drug, bound to enzyme topoisomerase IIα inhibitor, and intercalates DNA topoisomerase IIα, preventing re-ligations in DNA strands fragmentation and disruption of DNA repair. The expression of this enzyme was used tumor cells marker because of its key function in cell proliferation. The cleavable complex of topoisomerase IIα is hypothesized to damage the DNA and may enhance apoptosis in tumor cell proliferation. The susceptibility of cells to mitoxantrone is associated with cell topoisomerase II α protein and lowered resistance in breast cancer line cell lines to topoisomerase IIα inhibitors. MT is an ABC-transporter in breast cancer, also designated to be associated with “Breast cancer resistance protein” (BCRP) and it is also a cell cycle non-specific anti-cancer drug and P-glycoprotein substrate. Multiple drug resistance is one of the major drawbacks of this drug which can be avoided by reducing the efflux of the drug from cancer cells by formulating drug by using lipophilic carriers. This manuscript discusses about MT's source, chemistry, physicochemical properties, anti-cancer effects of mitoxantrone and possible pathways, Mitoxantrone targeting topoisomerase II inhibitor for cancer therapy and its mechanism, Various Nano formulation development strategy, toxicity profile, and a few patents related information.

Antimycobacterial Activity, Synergism, and Mechanism of Action Evaluation of Novel Polycyclic Amines against Mycobacterium tuberculosis.

Mycobacterium tuberculosis has developed extensive resistance to numerous antimycobacterial agents used in the treatment of tuberculosis. Insufficient intracellular accumulation of active moieties allows for selective survival of mycobacteria with drug resistance mutations and accordingly promotes the development of microbial drug resistance. Discovery of compounds with new mechanisms of action and physicochemical properties that promote intracellular accumulation, or compounds that act synergistically with other antimycobacterial drugs, has the potential to reduce and prevent further drug resistance. To this end, antimycobacterial activity, mechanism of action, and synergism in combination therapy were investigated for a series of polycyclic amine derivatives. Compound selection was based on the presence of moieties with possible antimycobacterial activity, the inclusion of bulky lipophilic carriers to promote intracellular accumulation, and previously demonstrated bioactivity that potentially support inhibition of efflux pump activity. The most potent antimycobacterial demonstrated a minimum inhibitory concentration (MIC99) of 9.6 μM against Mycobacterium tuberculosis H37Rv. Genotoxicity and inhibition of the cytochrome bc1 respiratory complex were excluded as mechanisms of action for all compounds. Inhibition of cell wall synthesis was identified as a likely mechanism of action for the two most active compounds (14 and 15). Compounds 5 and 6 demonstrated synergistic activity with the known Rv1258c efflux pump substrate, spectinomycin, pointing to possible efflux pump inhibition. For this series, the nature of the side chain, rather than the type of polycyclic carrier, seems to play a determining role in the antimycobacterial activity and cytotoxicity of the compounds. Contrariwise, the nature of the polycyclic carrier, particularly the azapentacycloundecane cage, appears to promote synergistic activity. Results point to the possibility of combining an azapentacycloundecane carrier with a side chain that promotes antimycobacterial activity to develop dual acting molecules for the treatment of Mycobacterium tuberculosis.

FLOATING MULTIPLE UNIT MINITABLETS OF METOPROLOL SUCCINATE: FORMULATION, IN VITRO AND IN VIVO CHARACTERIZATION

Objective: In this present research, formulation of floating multiple unit minitablets of metoprolol succinate without using gas generating agent was attempted with an objective of increased residence time, sustained release, and improved oral bioavailability.
 Methods: Solid dispersions were prepared with lipophilic carriers such as compritol ATO888, Gelucire 43/01, Gelucire 39/01, and precirol ATO 05 was formulated using fusion technique. Neusillin US2 was used as an adsorbent. The solid dispersions were compressed into minitablets, weighing 20 mg, and then filled into ‘0’ size capsule.
 Results: Formulation F9, F10, F14, and F15 showed instantaneous floating lag time, i.e., 0 min, floating time more than 12 h, and sustained release up to 12 h. Pharmacokinetic study of the optimized formulation (F9) showed 2.46 times increase in area under the curve with increased residence time.
 Conclusion: Hence gelucire 43/01 based floating multiple unit minitablets of metoprolol succinate can be considered a promising approach.

Interaction of limonene, terpineol, and 1,8 cineol with a model of biomembrane: A DSC study

The interaction of limonene, terpineol, and 1,8 cineol with a model of biological membrane and the absorption of the three compounds by the same model of biological membrane were studied. In addition, the possibility to use a lipophilic carrier for the transport and delivery of the compounds to the biomembrane was investigated. Differential scanning calorimetry technique was used. The obtained results reveal that all the compounds interact and are absorbed by the model of biomembrane with different extent depending on their characteristics. Moreover, the lipophilic carrier could be used as a suitable system for the transport and delivery of such compounds to biomembranes.

Clinical outcomes after permanent polymer or polymer-free stent implantation in patients with diabetes mellitus: The ReCre8 diabetes substudy.

ObjectivesThe purpose of this analysis was to compare target‐lesion failure (TLF) of a permanent polymer zotarolimus‐eluting stent (PP‐ZES) versus a polymer‐free amphilimus‐eluting stent (PF‐AES) in diabetics.BackgroundThe improvement of outcomes with new‐generation drug‐eluting stent as seen in the general population is less pronounced among diabetics. The PF‐AES introduces an elution‐technology with potential enhanced performance in diabetics.MethodsIn this subanalysis of the ReCre8 trial, patients were randomized to either a PP‐ZES or PF‐AES after stratification for diabetes and troponin status. The primary device‐oriented endpoint was TLF, a composite of cardiac death, target‐vessel myocardial infarction and target‐lesion revascularization.ResultsIn the ReCre8 trial, 304 (20%) patients were diabetic and 96 (6%) had insulin‐dependent diabetes mellitus. There was no statistically significant difference between the two study arms regarding the primary endpoint (PP‐ZES 7.2% vs. PF‐AES 4.0%; p = .21), although the composite of net adverse clinical events was higher in the PP‐ZES arm (15.7 vs. 8.0%; p = .035). Stent thrombosis was low in both groups with no cases in the PP‐ZES arm and 1 case in the PF‐AES arm (p = .32). Regarding insulin‐treated diabetics, TLF was higher in the PP‐ZES arm (14.9 vs. 2.1%; p = .022).ConclusionsDiabetics could potentially benefit from a dedicated stent, releasing sirolimus with a lipophilic carrier (amphilimus‐formulation). Future trials should confirm the potential benefit of a PF‐AES in this population.

Formulation and development of floating multiple-unit minitablets of Nimodipine without using a gas-generating agent: in vitro and in vivo characterization

BackgroundFloating drug delivery systems have been reported for different active pharmaceutical ingredients as single-unit tablets with gas-generating agents. In this present research, the formulation of floating multiple-unit minitablets of Nimodipine without using gas-generating agent was attempted with an objective of increased residence time, sustain-release and improved oral bioavailability. Solid dispersion with different ratios (1:0.5, 1:1, 1:1.5, 1:2, 1:2.5) of drug with the lipophilic carrier such as Compritol ATO 888, Gelucire 43/01, G39/01 and Precirol ATO 05 was formulated using melt granulation technique. The adsorbent Sylysia 350 to lipophilic carrier is maintained at 1:1. The granules were compressed into minitablets weighing 15 mg and were filled into a ‘0’ size capsule.ResultsDifferential scanning calorimetry study justified no interaction of the drug with excipients. The formulations which exhibited desirable flow property, floating lag time less than 1 min and floating time of 12 h were further characterized for various post-compression parameters. The optimized single-dose (capsule) of floating multiple-unit minitablets of Nimodipine consisting of 60 mg of drug, 120 mg of G43/01 and 120 mg of Sylysia 350 showed an average of floating lag time within 24.48 s, floating time of 14.32 h and sustained-release up to 12 h. Pharmacokinetic study of the optimized formulation (F9) showed nearly 2.5 times increase in area under the curve with increased residence time in comparison to aqueous suspension of Nimodipine. The stability study revealed no significant change in various parameters before and after storage.ConclusionHence, gelucire 43/01-based multiple-unit minitablets of Nimodipine can be considered a promising approach for sustaining the drug release with gastric retention for 12 h without using gas-generating agent.

Phase transfer of metal cations by induced dynamic carrier agents: biphasic extraction based on dynamic covalent chemistry.

In contrast to the classical method where a single molecule is designed to extract metal cations under specific conditions, dynamic covalent chemistry provides an approach based on the implementation of an adaptive dynamic covalent library for inducing the generation of the extractant species. This approach has been applied to the liquid–liquid extraction of copper(ii) nitrate based on a dynamic library of acylhydrazones constituents that self-build and distribute through the interface of a biphasic system. The addition of copper(ii) cations to this library triggers a modification of its composition and the up-regulation of the ligand molecules driven by coordination to the metal cations. Among these, one species has proven to be sufficiently lipophilic to play the role of carrier agent and its formation by component exchange enables the partial extraction of the copper(ii). The study of different pathways to generate the dynamic covalent library demonstrates the complete reversibility and the adaptability of the system. The detailed analytical investigation of the system provides a means to assess the mechanism of the dynamic extraction process.

Integrative physicochemical and HPLC assessment studies for the inclusion of lornoxicam in buffalo's milk fat globules as a potential carrier delivery system for lipophilic drugs

Searching for safe and effective drug delivery carriers has gained a lot of demand in recent years. This is why natural carriers become the target of researchers working in that field. In this study, buffalo's milk is investigated as a natural lipophilic carrier for the delivery of a model lipophilic drug, lornoxicam (LOR). LOR has been loaded into milk fat globules via homogenization. The homogenized fat globules and casein micelles were characterized for their size, charge, surface morphology, and entrapment efficiency of LOR into fat globules. A new HPLC-UV detection method coupled with liquid-liquid extraction (LLE) procedure was developed and fully validated for the quantitative determination of LOR in fat globules. Results showed that dynamic light scattering of blank and loaded fat globules had a similar particle sizes of 3.42±2.80 and 3.61±0.20 µm, respectively, proving that the medicated casein micelles regained its nanostructure after entrapping LOR. Furthermore, they have a polydispersity index of 0.21 and 0.27, respectively, which revealed their homogeneity. Transmission electron microscope images showed irregularly rounded or cubical non-aggregated fat globules loaded LOR where the blank ones were spherical. The change in surface morphology is attributed to the incorporation of LOR in fat globules. The developed HPLC-UV method showed a linear response for LOR in the range of 0.01-100 µg/mL with a high correlation coefficient of 0.998, and an excellent detection limit of 0.002 µg/mL. Moreover, the mean recoveries of LOR from whole milk samples ranged from 86.5% to 100.1% using the adopted LLE procedure. The entrapment efficiency for LOR in the milk fat globules was calculated using the developed HPLC-UV and LLE method. It was found to be approximating 100 % whereas, there was no drug detected in the skimmed milk portion. In conclusion, the fat portion of the milk could be considered as a potential nanocarrier and extremely stable colloidal dispersion system for the delivery of lipophilic drugs such as LOR.

DSC studies on the interaction of lipophilic cytarabine prodrugs with DMPC multilamellar vesicles

Cytarabine (1-β-d-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is used for the treatment of both acute and chronic myeloblastic leukemias and non-Hodgkin lymphoma. It has a very short plasma half-life and a very low oral bioavailability. To overcome these disadvantages, much effort has been focused on the design of cytarabine prodrugs. In this study, we have synthesized four different cytarabine prodrugs in order to increase the drug lipophilicity and the affinity of the prodrugs toward the biological membranes, as well as the lipophilic carriers. Differential scanning calorimetry was used to study the interaction of cytarabine and its prodrugs with multilamellar vesicles (MLVs) made of dimyristoylphosphatidylcholine (DMPC) and used as a model of biomembranes as well as a lipophilic carrier. The results showed that the 4-N-acetyl-2′,3′-5′-acetyl derivative and the prodrug with short chain fatty acids do not have a significant affinity with MLVs, whereas the prodrugs with long chain fatty acids have a stronger affinity with the MLVs with respect to cytarabine. The entity of the affinity depends on the fatty acids length. The increased affinity could be due to the fatty acid moieties which allow the molecule to insert among the phospholipid molecules. These results provide information on the interaction of these prodrugs with biomembranes and could be useful to design liposomes as carriers for the prodrugs.

Lipocalin-Like Prostaglandin D Synthase but Not Hemopoietic Prostaglandin D Synthase Deletion Causes Hypertension and Accelerates Thrombogenesis in Mice.

Prostaglandin (PG) D2 is formed by two distinct PGD synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD2-producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a σ glutathione-S-transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of L-PGDS– and H-PGDS–dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDS, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds knockout (KO) mice. Deletion of L-Pgds depresses urinary PGD2 metabolite (PGDM) by ∼35%, whereas deletion of H-Pgds does so by ∼90%. Deletion of L-Pgds, but not H-Pgds, elevates BP and accelerates the thrombogenic occlusive response to a photochemical injury to the carotid artery. HQL-79, a H-PGDS inhibitor, further depresses PGDM in L-Pgds KO mice, but has no effect on BP or on the thrombogenic response. Gene expression profiling reveals that pathways relevant to vascular function are dysregulated in the aorta of L-Pgds KOs. These results indicate that the functional impact of L-Pgds deletion on vascular homeostasis may result from an autocrine effect of L-PGDS–dependent PGD2 on the vasculature and/or the L-PGDS function as lipophilic carrier protein.

Abstract P1-10-16: In vitro delivery of model fluorescent dyes through the mammary papilla

Abstract In the United States, 100,000 women each year are diagnosed with atypical hyperplasia (AH), significantly increasing their risk of developing breast cancer. However, only 40% of patients accept breast cancer preventive treatment, in part, due to systemic side effects. The localization of pre-cancerous cells within the ducts or lobules of the breast permits a local treatment strategy employing the innate mammary ducts. This expansive tree-like structure extends throughout the entire breast and may serve as a conduit for local delivery of therapeutics, thereby minimizing side effects associated with current preventive treatment strategies. This study examines how lipophilicity influences diffusion through porcine tissue using a model hydrophilic dye, Sulforhodamine B (SRB), and a model lipophilic dye, Nile Red (NR). Porcine nipple or skin tissue was positioned in a Franz diffusion cell and the formulations were applied topically. With equivalent dye concentrations applied to the donor surface, we noted no significant difference in total dye permeation when comparing diffusion through skin versus nipple tissue or when comparing SRB versus NR after 48 hours. However, the diffusion coefficient for both NR and SRB through the nipple was almost 700-fold greater compared to through the skin indicating improved drug delivery via the nipple. Additionally, after 48 hours there was significantly higher retention of SRB in the nipple and skin compared to NR. When we further looked at the distribution of each dye within the nipple using fluorescence microscopy, we saw a distinction in the localization of each dye. Fluorescence micrographs show that lipophilic NR is retained within the ducts while the hydrophilic SRB diffuses throughout the entire tissue section, suggesting that hydrophobicity impacts the ability of molecules to diffuse from the duct into the surrounding tissue. This suggests that lipophilic carriers may be effective for delivery of cancer therapeutics or preventative agents targeting the mammary ducts, where AH is localized. Citation Format: Kurtz SL, Lawson LB. In vitro delivery of model fluorescent dyes through the mammary papilla [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-16.

Interphotoreceptor retinoid–binding protein removes all-trans-retinol and retinal from rod outer segments, preventing lipofuscin precursor formation

Interphotoreceptor retinoid-binding protein (IRBP) is a specialized lipophilic carrier that binds the all-trans and 11-cis isomers of retinal and retinol, and this facilitates their transport between photoreceptors and cells in the retina. One of these retinoids, all-trans-retinal, is released in the rod outer segment by photoactivated rhodopsin after light excitation. Following its release, all-trans-retinal is reduced by the retinol dehydrogenase RDH8 to all-trans-retinol in an NADPH-dependent reaction. However, all-trans-retinal can also react with outer segment components, sometimes forming lipofuscin precursors, which after conversion to lipofuscin accumulate in the lysosomes of the retinal pigment epithelium and display cytotoxic effects. Here, we have imaged the fluorescence of all-trans-retinol, all-trans-retinal, and lipofuscin precursors in real time in single isolated mouse rod photoreceptors. We found that IRBP removes all-trans-retinol from individual rod photoreceptors in a concentration-dependent manner. The rate constant for retinol removal increased linearly with IRBP concentration with a slope of 0.012 min-1 μm-1 IRBP also removed all-trans-retinal, but with much less efficacy, indicating that the reduction of retinal to retinol promotes faster clearance of the photoisomerized rhodopsin chromophore. The presence of physiological IRBP concentrations in the extracellular medium resulted in lower levels of all-trans-retinal and retinol in rod outer segments following light exposure. It also prevented light-induced lipofuscin precursor formation, but it did not remove precursors that were already present. These findings reveal an important and previously unappreciated role of IRBP in protecting the photoreceptor cells against the cytotoxic effects of accumulated all-trans-retinal.

Amphiphilic naproxen prodrugs: differential scanning calorimetry study on their interaction with phospholipid bilayers

Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers. The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied. Naproxen conjugation to lipoamino acids improves its interaction with biomembrane models and affects the transfer from a lipophilic carrier to biomembrane model. LAA portion may localize between the phospholipid chains; the entity of the interaction depends not only on the presence of the spacer but also on the LAA chain length. Variation of LAA portion can modulate the naproxen prodrugs affinity towards the biological membrane as well as towards the lipophilic carrier.

Delivering FLT to the Central Nervous System by Means of a Promising Targeting System: Synthesis, [11C]Radiosynthesis, and in Vivo Evaluation.

The development of delivery systems to transport some specific radiotracers across the blood-brain barrier (BBB) needs to be investigated for brain imaging. [18F]FLT (3'-deoxy-3'-18F-fluoro-l-thymidine), an analogue substrate of the nucleoside thymidine, has been developed as a proliferation tracer for oncological PET studies. Unfortunately, low-grade brain tumors are poorly visualized due to the low uptake of [18F]FLT in brain tissue, preventing its use in PET imaging to detect brain tumors at an early stage. Based on our previous work, a redox chemical delivery system (CDS) related to Bodor's strategy was developed to enable the penetration of FLT into the brain. To this end, FLT was covalently linked to a series of lipophilic carriers based on a 1,4-dihydroquinoline structure. To determine the best carrier, various sets of [11C]CDS-FLT were prepared and injected into rats. Pleasingly, in vivo results let us suggest that this CDS is a promising approach to overcome the BBB to target low-grade brain tumors for PET imaging.

Another step toward DNA selective targeting: Ni(II) and Cu(II) complexes of a Schiff base ligand able to bind gene promoter G-quadruplexes.

DNA G-rich sequences are able to form four-stranded structures organized in stacked guanine tetrads. These structures, called G-quadruplexes, were found to have an important role in the regulation of oncogenes expression and became, for such a reason, appealing targets for anticancer drugs. Aiming at finding selective G-quadruplex binders, we have designed, synthesized and characterized a new water soluble Salen-like Schiff base ligand and its Ni(II) and Cu(II) metal complexes. UV-Vis, circular dichroism and FRET measurements indicated that the nickel complex can stabilize oncogene promoter G-quadruplexes with high selectivity, presenting no interactions with duplex DNA at all. The same compound exhibited dose-dependent cytotoxic activity in MCF-7 breast cancer cells when combined with lipofectamine as lipophilic carrier.